Author ORCID Identifier
Semester
Summer
Date of Graduation
2023
Document Type
Dissertation
Degree Type
PhD
College
School of Medicine
Department
Biochemistry
Committee Chair
David Smith
Committee Member
Candice Brown
Committee Member
Justin Legleiter
Committee Member
Aaron Robart
Committee Member
Maxim Sokolov
Abstract
Maintaining protein homeostasis, or proteostasis, is crucial for cellular function, and protein degradation through the proteasome plays a pivotal role in this process. Dysregulation of the proteasome can lead to proteostasis collapse and has been linked to the development of neurodegenerative diseases and cancers. Neurodegenerative diseases often exhibit proteasome impairment, whereas proteasome upregulation is frequently observed in cancer. Although the use of proteasome inhibitors as a pharmaceutical approach has shown success in certain cancers, it has yet to demonstrate efficacy in neurodegenerative diseases due to the absence of drug-like small molecules capable of effectively reversing proteasome impairment and/or activating the proteasome. To address this challenge, we conducted a study focused on understanding and emulating the HbYX-dependent mechanism of proteasome activation utilized by endogenous complexes known as Proteasome Activators. Through this investigation, we characterized and elucidated the mechanistic details of a small molecule called ZYA, which stimulates peptide and protein degradation by the proteasome. ZYA served as a research tool to investigate the HbYX-dependent mechanism, leading to the identification of critical conformational changes in the proteasome and the discovery of novel binding pockets for small molecules. While proteasome inhibitors are currently utilized in clinical settings, there is a growing concern regarding the development of resistance to these inhibitors, necessitating the development of novel proteasome inhibitors. We identified an unparalleled mechanism of regulation by reverse T3, a thyroid hormone variant, with the aim of designing similar small molecules that can specifically and robustly inhibit the proteasome. The findings presented in these studies provide a framework for the development of proteasome activators and inhibitors, offering potential therapeutic strategies for neurodegenerative diseases and cancer. Overall, this research contributes to the search for effective therapeutic interventions by shedding light on the design of proteasome-targeting compounds that can either activate or inhibit the proteasome, depending on the specific pathological context, ultimately aiding in the treatment of neurodegenerative diseases and cancer.
Recommended Citation
Chuah, Janelle Joo Yee, "Elucidating mechanisms of proteasome modulation by small molecules to treat neurodegenerative diseases and cancer" (2023). Graduate Theses, Dissertations, and Problem Reports. 12100.
https://researchrepository.wvu.edu/etd/12100
Embargo Reason
Publication Pending